Kallee Govind, Milano Gérard, Duffaud Florence, Dahan Laetitia, Ciccolini Joseph
PRISM, Biogenopôle La Timone University Hospital of Marseille, Marseille, France.
COMPO, Inserm U1068 CRCM, Marseille, France.
Fundam Clin Pharmacol. 2025 Aug;39(4):e70035. doi: 10.1111/fcp.70035.
Anticancer drug 5FU is extensively metabolized by dihydropyrimidine dehydrogenase (DPD), an enzyme with high interindividual variability. Poor metabolizer (PM, i.e., DPD deficient) patients are at risk of life-threatening toxicities. Whether ultra-rapid metabolizer (UM) status could conversely compromise 5FU efficacy remains to be investigated.
In this real-world study, 352 adult patients treated with a 5FU-containing regimen were screened. Patients were classified as normal (extensive metabolizer, EM), PM, or UM on DPD function based upon baseline plasma uracil monitoring. The impact of DPD status on efficacy and safety endpoints was investigated.
Patients were categorized on DPD as UM (11.9%), EM (75.9%), and PM (12.2%). The response rate was 54.5%, with median PFS and OS of 13.9 and 19 months, respectively. PM patients were treated with an average 13% lower 5FU starting dose. There was no statistical difference in efficacy between UM and other patients. Severe toxicities were observed in less than 5% of patients, an incidence significantly lower than commonly reported with 5FU-containing regimen and was comparable between UM, EM, and PM patients. Our observations suggest that UM status is not associated with the lack of efficacy of 5FU. In addition, upfront DPD testing with adaptive dosing helps to reduce the incidence of severe toxicities, as PM patients on reduced doses did not have more severe toxicities than other patients treated with standard doses, while exhibiting similar efficacy in terms of response rate and survival.
When upfront DPD screening with adaptive dosing is performed, no difference is observed between UM, EM, and PM patients in terms of efficacy and safety.
#PADSA3GKW7.
抗癌药物5-氟尿嘧啶（5FU）主要由二氢嘧啶脱氢酶（DPD）代谢，该酶在个体间存在高度变异性。代谢不良者（PM，即DPD缺乏者）患者有发生危及生命毒性的风险。超快速代谢者（UM）状态是否会相反地损害5FU疗效仍有待研究。
在这项真实世界研究中，对352例接受含5FU方案治疗的成年患者进行了筛查。根据基线血浆尿嘧啶监测，将患者按DPD功能分为正常（广泛代谢者，EM）、PM或UM。研究了DPD状态对疗效和安全性终点的影响。
患者按DPD分类为UM（11.9%）、EM（75.9%）和PM（12.2%）。缓解率为54.5%，中位无进展生存期和总生存期分别为13.9个月和19个月。PM患者接受的5FU起始剂量平均低13%。UM与其他患者在疗效上无统计学差异。不到5%的患者观察到严重毒性，发生率显著低于含5FU方案通常报告的发生率，且UM、EM和PM患者之间相当。我们的观察结果表明，UM状态与5FU疗效缺乏无关。此外，采用适应性给药的预先DPD检测有助于降低严重毒性的发生率，因为剂量降低的PM患者与接受标准剂量治疗的其他患者相比，没有更严重的毒性，同时在缓解率和生存率方面表现出相似的疗效。
当进行采用适应性给药的预先DPD筛查时，UM、EM和PM患者在疗效和安全性方面未观察到差异。
#PADSA3GKW7。
